Human cytomegalovirus (HCMV) is a ubiquitous human pathogen, which in healthy individuals presents as an asymptomatic infection and is successfully controlled by the immune system. HCMV is able to persist within the submandibular gland (SMG) of the salivary gland for a few months before entering a latency period, after which it can periodically and asymptomatically reactivate. However, certain populations are highly vulnerable. For neonates and immunocompromised individuals, both primary and reactivated infections can be extremely dangerous due to their decreased immune health. The role of CMV-specific CD8+ T cells has been extensively studied. Conversely, the function of non-classical CD8+ T cells has not been examined. Murine CMV is a well-established model to study HCMV infections, owing to its similar pathogenesis, persistence, and ability to undergo latency and reactivation. Using this model, our preliminary data demonstrate that non- classical CD8+ T cells expand in response to MCMV, become activated, and secrete inflammatory cytokines. My preliminary data also exclude CD1d as the restricting element, but support a role for the non-classical MHC molecule, Qa-1. Based on these data, I propose to determine the role of non- classical CD8+ T cells during MCMV challenge and to identify their restricting element and ligand. In Specific Aim 1, I will determine the MHC class Ib restriction molecule necessary for non-classical CD8+ T cell expansion during MCMV infection, as well as the recognized ligand. In Specific Aim 2, I will determine the specific role of MCMV expanded non-classical CD8+ T cells. The proposed experiments will help elucidate the immunological role of non-classical CD8+ T cells and the immune response to CMV infections, a necessity to help limit the complications seen in immunocompromised individuals and neonates.